JP2703193B2 - Method for resolving a racemic mixture of cis compounds of 2-diphenylmethyl-N-[(2-methoxyphenyl) methyl] -1-azabicyclo [2,2,2] octane-3-amine - Google Patents

Abstract

Azabicyclo[2.2.2]octan-3-imines of the general formula <IMAGE> I wherein R1, R2 and R3 are as defined herein are prepared by reacting a compound of the formula <IMAGE> II with a compound of the formula <IMAGE> III wherein A is MgCl, MgBr or Li.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a substituted 2-diphenylmethyl-N-substrate having substance P activity.
The present invention relates to a method for resolving a racemic mixture of a cis compound of [(2-methoxyphenyl) methyl] -1-azabicyclo [2,2,2] octane-3-amine. The racemate is
Azabicyclo [2,2,2] octane-3 as an intermediate
-Can be produced from imines. The intermediate azabicyclo [2,
2,2] Octane-3-imines can be prepared from phenylmethylimine intermediates.

[0002] The above-mentioned racemates, their production methods and their ability to antagonize substance P are disclosed in WO 90/05729. These compounds are effective in treating diseases caused by excess substance P. Substance P is a naturally occurring undecapeptide belonging to the tachykinin-based peptides, and tachykinin-based peptides are so named for their rapid stimulatory effect on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide produced in mammals (essentially isolated from the intestine) and has a characteristic amino acid sequence. The extensive involvement of substance P and other tachykinins in the pathophysiology of many diseases has been well documented in the art. Examples of such diseases are psychosis, migraine, rheumatoid arthritis and ulcerative colitis.

[0003]

The problem to be solved by the present invention is as follows:

Embedded image Racemic mixture of the compound - cis shown in (-) is reacted with mandelic acid, of the formula VII the compound (-) was purified mandelate, (-) mandelate processes, of the formula VII - the () The present invention relates to a method for resolving the racemate by recovering the compound.

The compound of formula VII can be prepared as follows.

First, the equation:

Embedded image And a compound represented by the formula:

Embedded image Wherein A is MgCl, MgBr or lithium.
By reacting with a compound represented by the formula:

Embedded image Is produced.

The compound of formula IIa has the formula:

Embedded image And a compound represented by the formula:

Embedded image By reacting with a compound represented by the formula:

Embedded image Can be obtained by producing the compound represented by

Next, the formula:

Embedded image Is further reduced with sodium triacetoxyborohydride and acetic acid to give a compound of the formula:

Embedded image To produce a racemic mixture of the cis compounds

[0008] reaction of the detailed description formula IIa compound of formula IIIa compounds of the invention is carried out in an inert solvent in the reaction, which can dissolve the Grignard reagent of formula IIIa. Suitable solvents are, for example, di (C ₁
-C ₆₎ ethers such as alkyl ethers or cyclic ethers such as tetrahydrofuran or dioxane. Other suitable solvents are toluene, dimethoxy-ethane and glyme. Mixtures of these solvents can be used as well. Reaction temperatures generally range from about 0 ° C to room temperature. Higher reaction temperatures of about 50 ° C. or higher can be used to increase the reaction rate.

The reaction of a compound of formula IVa with a compound of formula Va
The reaction is carried out in a solvent inert to the reaction, for example, an aromatic hydrocarbon (eg, toluene, xylene or benzene). The reaction is generally carried out at a temperature in the range from room temperature to the reflux temperature of the solvent inert to the reaction. During this reaction, an acid catalyst is generally present. Examples of such catalysts are sulfonic acids such as, for example, camphorsulfonic acid and p-toluenesulfonic acid.

The reduction of a compound of formula Ia with sodium triacetoxyborohydride and acetic acid is generally from about 5 to about 50.
C., usually at about 20 to about 25C, for example at room temperature.

The reaction of the compound of formula VII with (-) mandelic acid is generally carried out in ethyl acetate. Subsequent purification is generally performed by slurrying the (-) mandelic acid salt at reflux in ethyl acetate. The purified salt is treated with a strong base to recover the (-) compound of formula VII. This treatment is generally performed at pH 10-12. Examples of strong bases are strong inorganic bases, such as, for example, alkali metal hydroxides (eg, potassium hydroxide) and alkali metal carbonates, such as, for example, potassium carbonate.

The final compounds of the present invention can be administered by the oral route at doses ranging from about 5.0 mg / day to about 1500 mg / day, as described in further detail in WO 90/05729. Can be administered by either the parenteral or topical route.

The activity of the final compounds of the invention as substance P antagonists makes the tachykinin receptor visible by autoradiography, due to their ability to block the binding of substance P at the substance P receptor site in bovine tail tissue. Is evaluated using a radioligand. The substance P antagonist activity of the quinuclidine compounds described herein is determined by Journal.
al of Biological Chemistr
y , vol. 258, p. 5158 (1983),
M. A. It is evaluated using standard analytical methods described by Cascieri et al. This method essentially determines the individual compound concentration required to reduce the amount of radiolabeled substance P ligand at the substance P receptor site of the isolated bovine tissue by 50%, thereby characterizing each test compound. It includes obtaining the IC _50.

The following examples illustrate the invention.

[0015]

EXAMPLES Example 1 A. N-[(2-methoxyphenyl) methyl] -2-f
Phenylmethylene-1-azabicyclo [2,2,2] -o
Cutane-3-imine mechanical stirrer, thermometer, cooling pipe, Dean S
In a 12 L three-neck round bottom flask (3 nrbf) equipped with a trap trap, 5.9 L of toluene, 791.8 g of 2-phenylmethylene-1-azabicyclo [2,2,2] -octane-3-imine (3.7 g). Mol), 764 g (5.6 mol, 1.5 equivalents) of 2-methoxybenzylamine, and 8.8 g (0.00) of (+) camphorsulfonic acid.
39 mol). The solution is refluxed (11
(6 ° C.) and refluxed for 42 hours. Dean Sta
A total of 75 ml of water was collected in the rk trap, indicating that the reaction was in progress. The solution containing the title product was cooled to room temperature.

When isolated, the following NMR data were obtained: ¹ H NMR (CDCl ₃ ): 8.05 (d, 2)
H), 7.40-6.80 (m, 9H), 4.80.
(S, 2H), 3.80 (s, 3H), 3.25-2.
95 (m, 5H), 1.90-1.70 (m, 4H).

B.2- (diphenylmethyl) -N-
[(2-Methoxyphenyl) methyl] -1-azabizik
B [2,2,2] -Octane-3-imine 3M phenylmagnesium bromide / diethyl ether at 5 ° C
-1.8L (5.6 mol, 1.5 equivalent)
In a 22 L three-necked flask, obtain the sample obtained in Part A of this example.
The solution was charged. This toluene solution has a temperature of 10
The addition was continued over 1.5 hours while maintaining the temperature below ° C.
After adding about half of the toluene solution, a tan slurry is formed.
Obtained. The reaction is stirred for 12-18 hours while warming to room temperature.
Stirred. Cool the tan slurry to 5 ° C. and add 6.1 L of water
Gradually stopped the reaction. Ce added to the stopped reaction
Add 500g of lite and warm it to 30 ° C,
Stirred at 30 ° C. for 30 minutes. This slurry is
Filtered through a lite and washed with toluene.
Separate the layers, wash the aqueous layer with 1 L of toluene,
Combine the layers and add 30 g with 500 g magnesium sulfate.
Dried for minutes. The slurry is filtered and the filtrate is concentrated.
Vacuum evaporated to an oily solid. This thick oily solid
Isopropanol (4.5 L) was added to the body,
Cool the rally to 5 ° C and granulate at this temperature for 1 hour
I let it. The solid is filtered off and 0.5 l of cold isopropanol is added.
Wash and evaporate in vacuo at 50 ° C. to give the title compound 4
94.9 g (30.5% over two steps) were obtained. Fusion
Point: 154-158 ° C.¹HNMR (CDCl_Three ):
7.45-6.70 (m, 14H), 4.65 (d, 1
H), 4.45 (q, 2H), 4.25 (d, 2H),
3.80 (s, 3H), 3.15-3.00 (m, 3
H), 2.70-2.35 (m, 2H), 1.85-
1.65 (m, 4H).

[0018]Example 2 2-diphenylmethyl-N-[(2-methoxyphenyl
L) Methyl] -1-azabicyclo [2,2,2] -oct
Tan-3-amine After charging 10.3 L of acetic acid to a 22 L three-necked flask
In addition, sodium triacetoxyborohydride 531.1 g
(2.5 mol) was added over 15 minutes. This solution
To the title compound of Example 1B, 411.5 g (1.0 mol)
Was added over 20 minutes. During this addition, the temperature was 25
C. to 30.degree. 3. Run the reaction at ambient temperature
Stirred for 5 hours, then concentrated to a thick oil.
This oil was separated into 3.1 L of methylene chloride and 6.3 L of water.
Arranged. The pH of this mixture is adjusted to 50% sodium hydroxide 6
Adjusted from 4.2 to 8.4 with 45 ml. Min layer
Separate and wash the aqueous layer with 1.4 L of methylene chloride.
Combine the layers and add 3
Dry for 0 minutes. The slurry is filtered and the filtrate is oily.
Vacuum evaporated to a solid. Isolate this oil
When diluted with 3.3 L of ethanol, a thick precipitate of white solid is formed.
occured. The slurry was heated to 35 ° C. under vacuum and the remaining
Remove the methylene chloride, cool to 5 ° C, and granulate for 30 minutes.
It was made. The white solid is isolated by filtration and the cold isop
Wash with lopanol, vacuum dry at 45 ° C.,
86.1% yield of 356 g of the title compound (racemic mixture)
I got it. The melting point was 133-135 ° C.

Example 3 (-)-2-diphenylmethyl-N-[(2-methoxy
Phenyl) methyl] -1-azabicyclo [2,2,2]
In a 22 L three-necked flask equipped with an octane-3-amine mechanical stirrer and a thermometer, 345 g of the title compound of Example 2 (0.8 g) was added.
4 mol) and 10.4 L of ethyl acetate. The reaction was stirred at 25 ° C. for 10 minutes resulting in a hazy solution. 127.2 g of (-) mandelic acid was added to this solution.
(0.84 mol) and about 4 at 20-25 ° C.
After stirring for minutes, a white slurry formed. The reaction mixture is stirred at this temperature for 2 hours, then the white solid is isolated by filtration, washed with ethyl acetate,
Air dried to give 386 g (81.8%) of the mandelic salt. This yield represents a 31.8% excess of the desired diastereomer salt with a theoretical yield of 236 g.

This salt was purified by the following method. Impurity mandelate (386 g) was added to 7.7 L of refluxing ethyl acetate.
Slurry for 45 minutes in 20-2 for 1 hour.
Cool to 5 ° C., filter and wash with about 1 L of ethyl acetate.
The solvent wet cake was dried in 5.5 L of refluxing ethyl acetate for 45 hours.
Slurried for 1 minute, cooled to 20-25 ° C. for 1 hour, filtered and washed with about 1 L of ethyl acetate. The solvent wet cake was slurried in 4.0 L of refluxing ethyl acetate for 45 minutes, cooled to 20-25 ° C. for 1 hour, filtered, washed with about 1 L of ethyl acetate, air-dried to give the desired diastereomer salt. 199.6 g (84.6% yield) were obtained. The specific rotation of this mandelic salt
rotation is [α] _D = −51.5 ° (CH ₂
Cl ₂ , c = 0.55) and the melting point is 196-198.
Met.

A 12 L three-necked flask was equipped with a mechanical stirrer, a thermometer, and a pH meter. In this flask, 198.6 g (0.35 mol) of purified mandelic acid salt, and 3.
97 L and 3.4 L of methylene chloride were charged. The pH of the biphasic mixture was 5.2, which was adjusted to pH 13-14 with 44 ml of 50% sodium hydroxide. The temperature during the addition of sodium hydroxide was 18 ° C. The layers were separated and the aqueous layer was washed with 1.7L of methylene chloride.
The organic layers were combined, backwashed with 2 L of water, dried over magnesium sulfate and filtered. The filtrate was concentrated to about 0.5 L in air and replaced with about 0.5 L of isopropanol to a 0.5 L volume and 60 ° C. temperature. An additional 0.5 L of isopropanol was added and the reaction was allowed to cool to 20-25 C over 1.5 hours. During this cooling period, a white slurry develops, which is isolated by filtration, washed with isopropanol and dried in vacuo to give, from 172.5 g possible from 345 g of the racemic starting material, the title compound which is the desired enantiomer 115.5 g (6
7.0% yield). The specific rotation of this substance is [α] _D
= -22.2 ° (CH ₂ Cl ₂ , c = 0.50) and the melting point was 155 ° -157 ° C.

Example 4 In a 5 L three-necked flask equipped with a mechanical stirrer, a thermometer, an addition funnel and a steam bath, 123.3 g (0.30 mol) of the title compound of Example 3 and acetone 3.
1 L was charged. 30 ° C for dissolving this slurry
And cooled again to 24 ° C. Acetone 25
58.6 g of methanesulfonic acid dissolved in 2 ml (0.6 g)
(0 mol) was added over 5 minutes. The reaction increased in temperature from 24 ° C. to 32 ° C., resulting in a thick white slurry.
This was stirred at ambient temperature for 2 hours. The reaction was concentrated to a slurry volume of 300-400 ml and a temperature of 60 ° C. in air. To this slurry was added 750 ml of methanol to dissolve the solid material. The solution was "filtered out" by filtration and 150-20
The mixture was concentrated in the atmosphere until the volume reached 0 ml. 500 ml of filtered isopropanol was added and the reaction was
Concentrated in vacuo to a volume of ml. A further 500 ml of filtered isopropanol was added and the reaction
and concentrated in vacuo to a temperature of 45 ° C. Upon cooling the reaction, crystallization occurred. The slurry was stirred for 1.5 hours while cooling to ambient temperature, then at 5 ° C. for 45 minutes. The product was isolated by filtration and the cake was washed twice with 200 ml of cold filtered isopropanol. After vacuum drying at 45 ° C. for 12 hours, 170.7 g of the methanesulfonate of the title product of Example 3
(94.4%) was obtained. Melting point 244.5-246
° C and the specific rotation is [α] _D = -25.8 ° (CH ₃
OH, c = 1.1).

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Martia Shaw, Charles Double, Norwich-Westerly Road, 06359, North Stonington, Connecticut, United States 274 (56) References JP-A-63-145256 (JP, A) JP-A-63-54342 (JP, A) JP-A-62-192362 (JP, A) JP-A-59-110656 (JP, A) International publication 90/5729 (WO, A)

Claims (2)

(57) [Claims] [Claim 1] The formula: Racemic mixture of the compound - cis shown in (-) is reacted with mandelic acid, of the formula VII the compound (-) was purified mandelate, (-) mandelate processes, of the formula VII - the () A method for resolving the above racemate by recovering the compound. 2. treating (-) mandelic acid salt with a strong base;
The method according to claim 1.